U.S. patent number 4,028,374 [Application Number 05/628,314] was granted by the patent office on 1977-06-07 for antibacterial thiocyanatobenzothiazoles.
This patent grant is currently assigned to Morton-Norwich Products, Inc.. Invention is credited to Robert James Alaimo, Stanford Salvatore Pelosi, Jr..
United States Patent |
4,028,374 |
Pelosi, Jr. , et
al. |
June 7, 1977 |
Antibacterial thiocyanatobenzothiazoles
Abstract
Certain thiocyanatobenzothiazoles of the formula: ##STR1##
wherein R is hydrogen, 4-bromo, 4-chloro, 4-fluoro, 3,4-dichloro or
4-nitro; R.sub.1 is methoxy or thiocyanato; R.sub.2 is n-butyl,
chloro, methyl, or thiocyanato; and R.sub.3 is hydrogen or chloro
are effective antibacterial agents.
Inventors: |
Pelosi, Jr.; Stanford Salvatore
(Norwich, NY), Alaimo; Robert James (Norwich, NY) |
Assignee: |
Morton-Norwich Products, Inc.
(Norwich, NY)
|
Family
ID: |
24518376 |
Appl.
No.: |
05/628,314 |
Filed: |
November 3, 1975 |
Current U.S.
Class: |
548/163 |
Current CPC
Class: |
C07D
277/82 (20130101) |
Current International
Class: |
C07D
277/82 (20060101); C07D 277/00 (20060101); C07D
277/82 () |
Field of
Search: |
;260/305 |
References Cited
[Referenced By]
U.S. Patent Documents
Primary Examiner: Daus; Donald G.
Assistant Examiner: Berch; Mark L.
Attorney, Agent or Firm: Franze; Anthony J.
Claims
What is claimed is:
1. A compound of the formula: ##STR3## wherein R is hydrogen,
4-bromo, 4-chloro, 4-flouro, 3,4-dichloro, or 4-nitro; R.sub.1 is
methoxy or thiocyanato; R.sub.2 is n-butyl, chloro, methyl, or
thiocyanato; R.sub.3 is hydrogen or chloro and at least one of
R.sub.1 and R.sub.2 is thiocyanato.
2. The compound
6-methyl-2-[3-(p-nitrophenyl)ureido]-4-thiocyanatobenzothiazole.
3. The compound
6-chloro-2-(3-phenylureido)-4-thiocyanatobenzothiazole.
4. The compound
6-chloro-2-[3-(p-chlorophenyl)ureido]-4-thiocyanatobenzothiazole.
5. The compound
2-[3-(p-bromophenyl)ureido]-4-methoxy-6-thiocyanatobenzothiazole.
6. The compound
2-[3-(p-bromophenyl)ureido]-6-(n-butyl)-4-thiocyanatobenzothiazole.
7. The compound
6,7-dichloro-2-[3-(p-chlorophenyl)ureido]-4-thiocyanatobenzothiazole.
8. The compound
2-[3-(p-bromophenyl)ureido]-6,7-dichloro-4-thiocyanatobenzothiazole.
9. The compound
6,7-dichloro-2-[3-(3,4-dichlorophenyl)ureido]-4-thiocyanatobenzothiazole.
10. The compound
6,7-dichloro-2-[3-(p-fluorophenyl)ureido]-4-thiocyanatobenzothiazole.
Description
This invention relates to chemical compounds. More particularly
this invention relates to certain thiocyanatobenzothiazoles of the
formula: ##STR2## wherein R is hydrogen; 4-bromo, 4-chloro,
4-fluoro, 3,4-dichloro, or 4-nitro; R.sub.1 is methoxy or
thiocyanato; R.sub.2 is n-butyl, chloro, methyl, or thiocyanato;
and R.sub.3 is hydrogen or chloro and a method for their
preparation.
The compounds of this invention possess antibacterial activity.
They are particularly inimical to Staphylococcus aureus and
Corynebacterium liquefacieus in the commonly employed in vitro
technique for determining antibacterial activity at levels of from
0.048 to 12.5 meg of compound per milliliter of test media. They
are thus adapted to be combined in various forms such as ointments,
powders, solutions, sprays, dusts and the like in a concentration
of from 0.1-1% by weight suitable for application to prevent
bacterial contamination.
The compounds of this invention are readily prepared. Currently it
is preferred to react the appropriate aniline with an alkali
thiocyanate, such as sodium, in the presence of bromine in an
alkanol carrier saturated with sodium bromide. Formation of the
urea is then accomplished in conventional fashion by reaction of
the 2-aminobenzothiazole with a phenyl isocyanate.
In order that this invention may be fully available to and
understood by those skilled in the art, the following examples are
supplied.
EXAMPLE 1
6-Methyl-2[3-(p-nitrophenyl)ureido]-4-thiocyanatobenzothiazole
A mixture of 2-amino-6-methyl-4-thiocyanatobenzothiazole (35 g.,
0.16 mole) in dimethylformamide (250ml.) was treated slowly with
p-nitrophenyl isocyanate (27 g., 0.16 mole). The reaction was then
heated under stirring on the steam bath for 5 hours. The mixture
was then filtered hot. The solution was chilled in an ice bath and
filtered. The product was combined with the solid initially
filtered to give 40 g. (65%) of off-white solid.
Recrystallization from ethanol-dimethylformamide provided an
analytical sample which melted at 283.degree.-284.degree. .
Anal. Calcd. for C.sub.16 H.sub.11 N.sub.5 O.sub.3 S.sub.2 : C,
49.86; H, 2.88; N, 18.17. Found: C, 49.73; H, 2.90; N, 18.12.
EXAMPLE II
6-Chloro-2-(3-phenylureido)-4-thiocyanatobenzothiazole
A mixture of sodium thiocyanate (200 g., 2.5 moles) in anhydrous
methanol (1200 ml.) was chilled to -7.degree. in a dry ice-acetone
bath. To the stirred mixture was added dropwise a chilled solution
of bromine (200 g., 1.25 moles) in sodium bromide saturated
methanol (300 ml.). The temperature is maintained between
-7.degree. and -10.degree. throughout the addition. After the
addition was complete, p-chloroaniline (65 g., 0.5 mole) was poured
into the mixture and the stirring continued at room temperature
overnight.
The reaction mixture was filtered and the solution poured into
water (3.1) and made basic with NH.sub.4 OH to precipitate
2-amino-6-chloro-4-thiocyanatobenzothiazole. The product was
removed by filtration, washed with water and ethanol and air dried.
The tan solid (90 g., 74%) was recrystallized from
dimethylformamide/water to provide an analytical sample which
melted at 205.degree.-207.degree. .
Anal. Calcd. for C.sub.8 H.sub.4 ClN.sub.3 S.sub.2 : C, 39.75; H,
1.67; N, 17.37. Found: C, 39.63; H, 1.97; N, 17.13.
A mixture of the above compound (36.5 g., 0.15 mole) in
dimethylformamide (500 ml.) was treated with phenyl isocyanate
(18.0 g., 0.15 mole) and was heated on a steam bath with stirring
for 5 hours. The mixture was poured into ice water (3 liters) and
the precipitated yellow solid was removed by filtration and air
dried to give 43 g. (79%) of product.
Several recrystallizations from dimethylformamide-methanol provided
an analytical sample which melted at 330.degree. with prior
softening. Anal. Calcd. for C.sub.15 H.sub.9 ClN.sub.4 OS.sub.2 :
C, 49.93; H, 251; N, 12.63. Found: C, 49.60; H, 2.51; N, 15.75.
EXAMPLE III
6-Chloro-2-[3-(p-nitrophenyl)ureido]-4-thiocyanatobenzothiazole
A mixture of 2-amino-6-chloro-4-thiocyanatobenzothiazole (36.5 g.,
0.15 mole) and p-chlorophenyl isocyanate (23 g., 0.15 mole) in
dimethylformamide (500 ml.) was heated on a steam bath with
stirring for 5 hours. The mixture was diluted with water to give a
yellow solid (40 g., 67%).
Recrystallization several times from nitromethane/dimethylformamide
provided an analytical sample which decomposed above 240.degree.
.
Anal. Calcd. for C.sub.15 H.sub.8 Cl.sub.2 N.sub.4 OS.sub.2 : C,
45.57; H, 2.04; N, 14.18. Found: C, 45.25; H, 2.07; N, 14.41.
EXAMPLE IV
2-[3-(p-Bromophenyl)ureido]-4-methoxy-6-thiocyanatobenzothiazole
To a stirred mixture of
2-amino-4-methoxy-6-thiocyanatobenzothiazole (48 g., 0.2 mole) in
320 ml. of dimethylformamide was added all at once
p-bromophenylisocyanate (40 g., 0.2 mole). After addition was
complete the stirred solution was heated on a steam bath for 5
hours. The solution was treated with water to the cloud point,
chilled, and then was filtered to give after air drying (77 g.,
88.5%) of yellow solid.
An analytical sample was prepared by one recrystallization from
methanol/dimethylformamide m.p. 245.degree.-247.degree. C.
Anal. Calcd. for C.sub.16 H.sub.11 BrN.sub.4 O.sub.2 S.sub.2 : C,
44.14; H, 2.55; N, 12.87. Found: C, 43.86; H, 2.58; N, 12.85.
EXAMPLE V
2-[3-(p-Bromophenyl)ureido]-6-(n-butyl)-4-thiocyanatobenzothiazole
A solution of NaSCN (81 g, 1.0 mole) in methanol (300 ml) was
chilled to -7.degree. in an ice-salt bath. The stirred solution was
treated dropwise with bromine (90 g, 0.57 mole) in NaBr saturated
methanol (150 ml). After all the bromine had been added,
p-butylaniline (30 g, 0.2 mole) was poured into the reaction
mixture. The mixture was stirred for 4.5 hours, then filtered and
poured into 400 ml of water. After neutralization with NH.sub.4 OH,
the 2-amino-6-(n-butyl)-4-thiocyanatobenzothiazole was removed by
filtration and recrystallized from methanol to give cream colored
needles (37 g, 71%) which melted at 167.degree.-169.degree. .
Anal. Calcd. for C.sub.12 H.sub.13 N.sub.3 S.sub.2 : C, 54.72; H,
4.97; N, 15.96. Found: C, 54.43; H, 4.97; N, 15.89.
To a stirred mixture of the above compound (53 g, 0.2 mole) in 320
ml. of dimethylformamide was added all at once p-bromophenyl
isocyanate (40 g, 0.2 mole). After addition was complete, the
stirred solution was heated on a steam bath for 4 hours. The
solution was then reacted with water to the cloud point, chilled,
and filtered to give after air drying (92 g, 99.3%).
An analytical sample was prepared by two recrystallizations from
methanol/dimethylformamide, two recrystallizations from acetic
acid, and one washing in hot nitromethane. The white solid melted
at 260.degree. C.
Anal. Calcd. for C.sub.19 H.sub.17 BrN.sub.4 OS.sub.2 : C, 49.48;
H, 3.71; N, 12.14. Found: C, 49.17; H, 3.77; N, 11.91.
EXAMPLE VI
6,7-Dichloro-2-[3-(p-chlorophenyl)ureido]-4-thiocyanatobenzothiazole
p-Chlorophenyl isocyanate (15.3 g., 0.10 mole) was added in
portions to a solution of 27.6 g. (0.10 mole) of
2-amino-6,7-dichloro-4-thiocyanatobenzothiazole in 300 ml. of
dimethylformamide. The solution was heated at 120.degree. with
stirring for 5 hours and then cooled at 0.degree. overnight. The
solid was collected by filtration to give 22 g. (51%) of product.
Recrystallization from ethanol gave an analytical sample, m.p.
238.degree.-239.degree. .
Anal. Calcd. for C.sub.15 H.sub.7 Cl.sub.3 N.sub.4 OS.sub.2 : C,
41.92; H, 1.64; N, 13.04. Found: C, 41.70; H, 1.66; N, 12.96.
EXAMPLE VII
2-[3-(p-Bromophenyl)ureido]-6,7-dichloro-4-thiocyanatobenzothiazole
p-Bromophenyl isocyanate (20 g., 0.10 mole) was added in portions
to a solution of 27.6 g. (0.10 mole) of
2-amino-6,7-dichloro-4-thiocyanatobenzothiazole in 300 ml. of
dimethylformamide. The solution was heated at 100.degree. with
stirring for 41/2 hours and cooled at 0.degree. overnight. The
solid was collected by filtration. The filtrate was poured into ice
water and the solid was collected by filtration. The combined
solids were recrystallized from a methanol-dimethylformamide-water
mixture to give 22 g. (50%) of product. Recrystallization from
ethanol gave an analytical sample, m.p. 243.degree.-245.degree.
.
Anal. Calcd. for C.sub.15 H.sub.7 BrCl.sub.2 N.sub.4 OS.sub.2 : C,
37.99; H, 1.49; N, 11.82. Found: C, 37.60; H, 1.45; N, 11.77.
EXAMPLE VIII
6,7-Dichloro-2-[3-(3,4-dichlorophenyl)ureido]-4-thiocyanatobenzothiazole
3,4-Dichlorophenyl isocyanate (18.8 g., 0.10 mole) was added in
portions to a solution of 27.6 g. (0.10 mole) of
2-amino-6,7-dichloro-4-thiocyanatobenzothiazole in 200 ml. of
dimethylformamide. The solution was heated at 110.degree. for 5
hours with stirring and cooled at 0.degree. overnight. The solid
was collected by filtration to give 28 g. (60%) of product. Two
recrystallizations from ethanol gave 13 g. (28%) of analytical
material, m.p. 313.degree.-320.degree. (dec.).
Anal. Calcd. for C.sub.15 H.sub.6 Cl.sub.4 N.sub.4 OS.sub.2 : C,
38.81; H, 1.30; N, 12.07. Found: C, 38.66; H, 1.35; N, 12.13.
EXAMPLE IX
6,7-Dichloro-2-[3-(p-fluorophenyl)ureido]-4-thiocyanatobenzothiazole
p-Fluorophenyl isocyanate (13.7 g., 0.10 mole) was added dropwise
to a solution of 27.6 g. (0.10 mole) of
2-amino-6,7-dichloro-4-thiocyanatobenzothiazole in 200 ml. of
dimethylformamide. The solution was heated at 120.degree. for 5
hours with stirring and was cooled at 0.degree. overnight. The
solid was collected by filtration to give 26 g. (63%) of product.
Two recrystallizations from nitromethane gave an analytical sample,
m.p. 308.degree.-310.degree. (dec.).
Anal. Calcd. for C.sub.15 H.sub.7 Cl.sub.2 FN.sub.4 OS.sub.2 : C,
43.59; H, 1.70; N, 13.56. Found: C, 43.23, H, 1.77; N, 13.55
* * * * *